Anatomy and function of the adult mammalian liver

2.3. Liver regeneration by hepatic oval stem cells 2.4. Serial Analysis of Gene Expression (SAGE)

2.1. Anatomy and function of the adult mammalian liver

The liver is not only the largest gland but also the biggest organ in mammalians.

Indeed, in the adult human the liver reaches a weight of 1.5 kilograms, and about 2% of the total body weight. The liver is located in the upper part of the abdominal cavity, just below the diaphragm, and on top of the stomach (Figure 1).

Figure 1. Anatomy of the human liver organ.

(Source: http://www.umm.edu/liver/liver.htm)

The microanatomical and functional unit of the liver is the hepatic lobule. The hepatic lobule has polygonal shape with a diameter of 1-2 mm and high of 2 mm.

The human liver is constituted by approximately 1 million of hepatic lobules. Each lobule is constituted by hepatic cords irradiating from the central vein or centrolobular vein. In the pig liver it is possible to observe easily the lobular structure which is delimited by connective tissue septa (Figure 2). The portal triad space is situated between the edges of the lobules and contains a portal vein branch, a hepatic artery branch, a bile duct and finally a lymphatic vessel.

Figure 2. In the pig liver it is possible to observe the morphology of the liver lobules.

(Source http://arbl.cvmbs.colostate.edu/hbooks/pathphys/digestion/index.html).

The liver has two separate afferent systems of blood supplies: the portal vein and the hepatic artery. The portal vein receives the blood from the intestine, stomach, spleen and pancreas. The portal vein system ramifies inside the liver in portal vein branches located between the interlobular spaces and the portal triad spaces.

From the portal veins branches are generated the hepatic sinusoids which are confluent in the central vein. The central veins from the liver lobules are connected with the hepatic veins, which are flowing into the vena cava inferior. The hepatic artery branches are also confluent in the sinusoids, thus the arterial blood and the portal venous blood flowing through the sinusoids to the central vein is mixed inside the lobule. Hence the lobules receive oxygenated blood from the hepatic artery and blood rich of nutrients from the hepatic vein.

The hepatocytes are the main liver cell population, and they are separated from the fenestrated sinusoid wall by the space of Disse. The space of Disse is important for the exchange of metabolites between the hepatocytes and the blood flow.

Figure 3. Liver blood supplies and bile duct system of the human liver.

(source: http://www.cincinnatichildrens.org/svc/prog/liver/liver-anatomy.htm).

On the opposite side of the sinusoids, the hepatocytes form the bile canaliculi which are connected to the canals of Hering and the interlobular bile ducts. The bile is drained from the bile canaliculi to the interlobular bile ducts in the opposite direction respect the blood stream. The bile ducts are connected to the right hepatic duct and left hepatic duct, which are confluent in the common hepatic duct.

From the common hepatic duct the cystic duct and the gallbladder originate (surprisingly none of them are present in the rat). The common hepatic duct continues in the common bile duct, from which the bile is secreted in the duodenum. The bile produced by the liver is important for the digestion, the absorption of lipids and fat soluble vitamins from the intestine (vitamin A, D, E and K), and for excretion of end products of the metabolism in the intestine.

The main cell type populations of the liver are the hepatocytes, the biliary cells, the stellate cells or Ito cells, the fibroblasts, the Kupffer cells, the vascular endothelial cells, and the leucocytes. The hepatocytes and the biliary cells have common embryonic origin from epithelial precursor cells, while the others cell types are mesenchymal derived.

The hepatocytes represent circa 80 to 90% of the liver weight and they are responsible for the exocrine liver function. The hepatocytes are important for many metabolic functions: 1) synthesis of plasma proteins like albumin, fibrinogen,

apolipoproteins, alpha globulins and gamma globulins, 2) metabolism of amino-acids (comprehending the urea metabolism), carbohydrates and lipids, 3) storage of many compounds like carbohydrates, iron and copper, 4) detoxification of drugs and toxic metabolites, 5) hormonal catabolism.

The biliary cells form the biliary ducts and ductules inside the liver. In particular, the biliary cells located in the ductules of Hering are believed to be the progenitors of the oval hepatic stem cell which will be discussed in this manuscript.

The Ito cells are located outside the sinusoids in the space of Disse, surrounding the hepatocytes with long processes, and they store almost 75% of the total body vitamin A as lipid droplets inside the cytoplasm. In addition, the Ito cells are involved in the regulation of hepatic growth and regeneration by secretion of cytokines and growth factors. Upon an injury, the Ito cells are activated, change their morphology from star-shaped to that typical of fibroblast or myofibroblast, loosing vitamin A. The strong phenotypic similarity between the fibroblasts and the activated Ito cells has led to confusion regarding the function and the characterisation of these two cell populations in the process of liver fibrosis.

Although authors are convinced that activated Ito cells can synthesize extra-cellular matrix proteins and trigger liver fibrosis (Friedman, 1997), we believe that the myofibroblasts are the most likely responsible for the generation of fibrotic tissue in the liver (Novosyadlyy et al., 2004;Ramadori and Saile, 2004).

The sinusoidal endothelial cells form the fenestrated sinusoids and are important for the blood supply from the hepatic arterial and venous system inside the lobules.

The Kupffer cells are immunitary cells with phagocytic activities. They represent the largest population of resident tissue macrophages in the animal body and are important for demolition of dead erythrocytes, and for the protection from micro-organism which penetrates from the colon organ to the portal blood flow. Finally, the leucocytes are immunitary cells important for the protection of the organ from viral and bacterial infections.